The MELAS mutation m.3243A > G alters the expression of mitochondrial tRNA fragments
Por:
Meseguer S, Navarro-González C, Panadero J, Villarroya M, Boutoual R, Sánchez-Alcázar JA and Armengod ME
Publicada:
1 sep 2019
Ahead of Print:
11 jun 2019
Resumen:
Recent evidences highlight the importance of mitochondria-nucleus communication for the clinical phenotype of oxidative phosphorylation (OXPHOS) diseases. However, the participation of small non-coding RNAs (sncRNAs) in this communication has been poorly explored. We asked whether OXPHOS dysfunction alters the production of a new class of sncRNAs, mitochondria] tRNA fragments (mt tRFs), and, if so, whether mt tRFs play a physiological role and their accumulation is controlled by the action of mt tRNA modification enzymes. To address these questions, we used a cybrid model of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), an OXPHOS disease mostly caused by mutation m.3243A > G in the mitochondrial tRNA(Leu(UUR)) gene. High-throughput analysis of small-RNA-Seq data indicated that m.3243A > G significantly changed the expression pattern of mt tRFs. A functional analysis of potential mt tRFs targets (performed under the assumption that these tRFs act as miRNAs) indicated an association with processes that involve the most common affected tissues in MELAS. We present evidences that mt tRFs may be biologically relevant, as one of them (mt i-tRF GluUUC), likely produced by the action of the nuclease Dicer and whose levels are Ago2 dependent, down-regulates the expression of mitochondria] pyruvate carrier 1 (MPC1), promoting the build-up of extracellular lactate. Therefore, our study underpins the idea that retrograde signaling from mitochondria is also mediated by mt tRFs. Finally, we show that accumulation of mt i-tRF GluUUC depends on the modification status of mt tRNAs, which is regulated by the action of stress-responsive miRNAs on mt tRNA modification enzymes.
Filiaciones:
:
RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain
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RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain
Panadero J:
Unidad de Genómica, Instituto de Investigación Sanitaria La Fe, Avenida Fernando Abril Martorell, 106 Torre A 7ª planta, Valencia 46026, Spain
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RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain
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RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain
Sánchez-Alcázar JA:
Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), and Centro de Investigación Biomédica en Red Enfermedades Raras, Instituto de Salud Carlos III, Sevilla 41013, Spain
:
RNA Modification and Mitochondrial Diseases Laboratory, Centro de Investigación Príncipe Felipe (CIPF), Carrer d'Eduardo Primo Yúfera 3, Valencia 46012, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) node 721, Madrid 28029, Spain
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